Hypertension has been recognized as a serious global public health problem, posing a considerable burden due to its widespread prevalence. An estimated 31.1% of adults (1.39 billion) worldwide had hypertension in 2010 (1). In China, among adults aged 35-75 year, nearly half have hypertension, less than a third are being treated, and fewer than one-twelfth are in control of their blood pressure (2). Hypertension is the leading preventable contributor to premature death and disability worldwide (3). It has been proved that hypertension is the major cause of high morbidity and mortality in cardiovascular diseases and stroke (4, 5). Additionally, hypertension, being a common chronic disease, negatively impacts the quality of life of hypertensive individuals compared to those with normal blood pressure (6). Despite the increasing prevalence and influence of hypertension has become a global challenge, hypertension is controllable and preventable. Timely intervention is an essential measure to reduce the incidence of hypertension and related events. Thus, it is important to identify the risk factors for development of hypertension.

Uric acid is the end product of purine metabolism generated during breakdown of nucleic acids and adenosine triphosphate, and also can be generated from degradation of a purine-rich dietary (7). In humans, due to the lack of urate oxidase, serum uric acid (SUA) can not be further degraded to allantoin, which is excreted freely in the urine (8). When the production of uric acid surpasses kidney excretion, the level of SUA will elevated, causing hyperuricemia (HUA). Growing evidence shows that HUA increases the risk of hypertension incidence (9). Several previous studies (10–12) have suggested that SUA is an independent risk factor for the onset and progression of hypertension. However, most of the relevant researches are cross-sectional studies and focus on identifying the association between baseline SUA and hypertension. Few studies explore the role of changes over time in SUA in the development of hypertension. Baseline SUA reflects the uric acid level at a specific point in time, but SUA levels are dynamic. Uncontrolled SUA levels are likely to further increase the risk of hypertension. Therefore, we conducted this study to investigate the potential impact of SUA, especially its change over time, on future hypertension incidence.

In this retrospective cohort study, we explored the relationship between the incidence of hypertension and the grades of SUA control. Our findings highlight a substantial elevation in the risk of developing hypertension among individuals with poor SUA control, irrespective of their baseline SUA levels. In addition, our results indicated that individuals presenting HUA at baseline faced a heightened risk of hypertension compared to those with normal baseline SUA levels when experiencing the same changes in SUA.

Recently, numerous studies have revealed the association between SUA and hypertension. A growing body of evidence suggests that SUA serves as an independent risk factor for the onset and progression of hypertension (10–12). In a meta-analysis encompassing 25 studies with 97,824 participants, the relative risk of incident hypertension was found to increase by 1.15 for every 1 mg/dl rise in SUA (9). Notably, SUA is a dynamic biochemical parameter that undergoes changes over time. A singular measurement of SUA at a specific time point may introduce bias to the relationship, as it fails to consider how SUA change within individual over time. Additionally, neglecting the potential impact of SUA changes and their association with future hypertension risk further compounds this bias. However, limited information is available on the association of change over time in SUA to hypertension incidence and blood pressure progression. Our research serves to supplement and provide new insights into this area. The Pressioni Arteriose Monitorate E loro Associazioni study (14) found that individuals who had a normal baseline SUA and developed HUA during a 25-year follow-up period showed higher 24-hour blood pressure. A prospective cohort study using trajectories to reflect an over 5-year change in SUA demonstrated distinct trajectories of uric acid were differentially associated with hypertension risk in middle-aged adults (15). Another prospective cohort study indicated that an increase in SUA over time could independently predict progression from prehypertension to hypertension, with an odds ratio of 1.41 in the highest quartile versus the lowest quartile (16). Our results were similar with these studies, showing that individuals with poorly controlled SUA faced a significantly higher risk of developing hypertension compared to those with optimally controlled SUA. A prior study with a large Korean cohort similarly indicated elevated risks for incident hypertension in the highest quartiles of SUA change compared to the lowest quartiles, supporting our findings (17).

In contrast to previous studies that assessed hypertension risk based on quartiles of SUA changes, our study adopted a novel practical classification method, categorizing SUA control into six grades. This classification considers whether baseline SUA was high and whether changes in SUA progressed to HUA or decreased to normal levels. To our knowledge, this is the first study to employ such a method to classify changes in SUA. Each category represented a distinct grade of SUA control, offering a more intuitive approach for conveying the risk of hypertension at different SUA change levels to the general population.

Notably, after adjusting for all confounding factors in Model 3, participants with normal baseline SUA levels that increased during follow-up exhibited an elevated risk of developing hypertension, even though their SUA levels remained within the normal range throughout. More interestingly, participants with baseline HUA whose SUA decreased to normal levels displayed a lower risk of incident hypertension compared to those with increased SUA levels during the follow-up period but still remaining within normal ranges. This underscores the critical role of good control of SUA, where a reduction from HUA at baseline to normal levels significantly diminishes the risk of hypertension. Conversely, an increase in SUA levels, even within the normal range, is associated with an elevated risk of hypertension. In addition, the linear associations persisted across various grades of SUA control, also emphasizing the importance of SUA management in the prevention of hypertension. Similar to our results, the Brisighella Heart Study (18) revealed a significant increase in SBP among individuals with worsened SUA levels. However, they simply categorized the population into groups based on uric acid changes: unchanged, elevated, or improved. In our study, when grouping participants, we considered whether their SUA levels deteriorated to hyperuricemia or improved to normal levels. This classification method was more detailed and practical.

Furthermore, an increased risk of hypertension was observed in participants with HUA at baseline compared to those with normal SUA at baseline when their changes in SUA were identical, implying that elevated baseline SUA levels also promoted the onset of hypertension. Thus, both elevated SUA levels at baseline and poor control of SUA can increased the risk of developing hypertension, which is consistent with the previous report (17). A prior study (19) has confirmed that the combined effect between increased baseline and changes in SUA is a significant and independent determinant for metabolic syndrome, providing evidence for our results.

Recently, the Uric Acid Right for Heart Health (URRAH) study proposed a lower SUA cutoff value, which may be more suitable for cardiovascular risk factors and cardiovascular mortality (20, 21). But we did not adopt this cutoff value for two main reasons. Firstly, there was a difference in the racial composition of the study populations. The URRAH study primarily included Italians, while our study focused on Chinese individuals. Different racial groups exhibit variations in SUA metabolism rates and disease incidence (22). Secondly, the observed outcomes of the studies were different. The URRAH study focused on cardiovascular mortality, while our study investigated the incidence of hypertension. Therefore, in our study, we conducted the analyses with the classical hyperuricemia cutoff value, which is widely used and accepted in China.

Subgroup analyses indicated that there was an interaction between SBP, DBP and grades of SUA control in the development of hypertension. When SBP <120 mmHg or DBP <80 mmHg, the risk of developing hypertension due to poor SUA control is higher. After excluding participants in prehypertension at baseline or participants who developed hypertension at the first follow-up, the sensitivity analyses further confirmed that the control of SUA was closely related to the risk of hypertension even though the blood pressure was at an ideal level. Participants with the best control had the lowest risk. These results are a reminder of the need to keep SUA under control even when blood pressure is normal.

The potential mechanisms of SUA contributes to the development of hypertension are multifaceted and complex. First, uric acid causes hypertension in the rat via activating the renin-angiotensin system inducing vascular smooth muscle cell proliferation, oxidative stress, and renal arteriolopathy (23–25). Second, HUA can induce endothelial dysfunction and renal vasoconstriction by inhibiting Nitric Oxide production. These factors cause renal structure abnormalities, resulting in salt-sensitive and uric acid-independent hypertension (26, 27). Third, the formation of uric acid is accompanied by the production of reactive oxygen species (28). Oxidative stress induced by reactive oxygen species can causes vascular dysfunction, cardiovascular remodeling, and renal dysfunction, leading to hypertension (29). In addition, many studies have suggested that uric acid–lowering medication can decrease blood pressure (30–32). Therefore, SUA is closely related to the development of hypertension.

The advantages of this study included a large sample size, a long follow-up period, and multiple follow-up measurements of SUA levels and blood pressure. Considering the impact of dynamic changes in SUA on the onset of hypertension, our results would be more reliable. The present study also has several limitations that need to be noted. First of all, this was a single-center study involving participants older than 40 years. Thus, the data predominantly reflect a specific demographic within a particular region, which might limit the generalizability of our findings to broader populations. Second, although we accounted for several confounding factors, certain potential factors influencing the development of hypertension, such as family history of hypertension, drinking and smoking, were not included in our analysis. Third, the results might be biased, because our study was a retrospective analysis. Finally, during the follow-up, some individuals who developed hypertension may have used diuretics and losartan to control blood pressure, and these medications can affect SUA levels (33, 34). However, information on these medication uses was not available, which could potentially impact our results.

In conclusion, poor SUA control increases risk for developing hypertension. Regardless of whether the initial SUA is normal or not, an increase in SUA over time rises the risk of developing hypertension. On this basis, initial high uric acid will further exacerbate this risk. Therefore, monitoring changes in SUA and implementing effective SUA control are important measures for primary prevention of hypertension.

Publicly available datasets were analyzed in this study. This data can be found here: https://doi.org/10.5061/dryad.z08kprrk1.

The original study, the source of our research data, involving humans was approved by Ethics Committee of Hangzhou Normal University School of Public Health (20220009). The protocol of this study was approved by the Ethics Committee of the Second Affiliated Hospital of Shantou University Medical College. No informed consent was required because the study was conducted retrospectively and anonymized.

ZYL: Conceptualization, Writing – original draft, Writing – review & editing. SW: Data curation, Methodology, Writing – review & editing. ZC: Investigation, Writing – review & editing. WL: Investigation, Writing – review & editing. ZHL: Data curation, Writing – review & editing. HS: Data curation, Writing – review & editing. DG: Conceptualization, Methodology, Supervision, Writing – review & editing.